Remedies for vertebral canal stenosis

ABSTRACT

The present invention relates to a preventive and/or therapeutic agent for spinal canal stenosis comprising aldose reductase inhibitory compounds. A representative example of aldose reductase inhibitory compounds is the compound represented by formula (I):  
                 
 
wherein all the symbols represent the same meaning as described in the specification; a salt of its acid when R 3a  represents hydrogen, or solvate thereof The therapeutic agent of the present invention is effective for prevention and/or therapy for spinal canal stenosis and the like, such as lumbar spinal canal stenosis.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for spinal canalstenosis. More specifically, the present invention relates to apreventive and/or therapeutic agent for spinal canal stenosis comprisingan aldose reductase inhibitory compound.

BACKGROUND ART

The internal space enclosed with each vertebral body and processusspinalis from the cervical vertebra to the sacral vertebra is calledspinal canal. The spinal canal stenosis shows various symptoms bynarrowing spinal canal due to the hypertrophic degeneration of thespine, one of constituents of spinal canal, and the yellow ligament anddue to the projection of the intervertebral disc etc., followed bycompressing the nerve tissue of the nerve root and the cauda equina,etc. The spinal canal stenosis is classified into the cervical spinalcanal stenosis, the thoracic spinal canal stenosis, the lumbar spinalcanal stenosis and the wide spinal canal stenosis by narrow parts ofspinal canal. Their symptoms by the nerve compression are lumber pain,upper or lower limbs pain, and numbness, etc. Especially, when the caudaequina nerve is injured, lumber pain, lower limbs pain, numbness andlanguidness deteriorate. This symptom is called an intermittentclaudication.

On the other hand, the aldose reductase is an enzyme that reduces aldosein the body, for example, glucose and galactose, to the correspondingpolyol, for example, sorbitol and garactitol. The sorbitol andgaractitol generated by a hyperactivation of this enzyme under theexcessive level of glucose concentration in diabetic patients and thelike are accumulated in the crystalline lens, the peripheral nerve andthe kidney, etc. And as a result, the complications of the retinopathy,the diabetic cataract, the peripheral neuropathy and the renal damage,etc. are caused. The aldose reductase inhibitors are known to beeffective for the treatment and the prevention of complications ofchronic diabetes mellitus by inhibiting the aldose reductase.

As aldose reductase inhibitors, for example, the following compounds areknown.

A compound represented by formula (I):

wherein all groups are the same meaning as described hereinafter; isreported to have inhibitory activity of aldose reductase and beeffective for a prevention and/or therapy of chronic diabeticcomplication, such as cardiovascular disease, nephropathy, retinopathy,diabetic cataract and neuropathy, and infection complication derivedfrom aldose reductase, such as neuralgic neuropathy, retinopathy,diabetic cataract and tubular renal disease-like nephropathy. (U.S. Pat.No. 4,464,382 and U.S. Pat. No. 4,831,045).

A compound represented by formula (II):

wherein all groups are the same meaning as described hereinafter; isreported to have inhibitory activity of aldose reductase and beeffective for a prevention and/or therapy of diabetic complication, suchas cataract, retinopathy, keratopathy, neuropathy and nephropathy(JP-A-5-186472 and JP-A-5-345784).

A compound represented by formula (III):

wherein all groups are the same meaning as described hereinafter; isreported to have inhibitory activity of aldose reductase and beeffective for a prevention and/or therapy of various diabeticcomplication, such as diabetic cataract, diabetic neuropathy, diabeticretinopathy and diabetic nephropathy.

A compound represented by formula (IV):

wherein all groups are the same meaning as described hereinafter; isreported to have inhibitory activity of aldose reductase and beeffective for a prevention and/or therapy of diabetic complication (U.S.Pat. No. 4,734,419 and U.S. Pat. No. 4,883,800).

However, it has never reported that compounds of aldose reductaseinhibitor are useful for spinal canal stenosis.

DISCLOSURE OF THE INVENTION

Therapy of spinal canal stenosis is surgery in severe case, andbasically conservative therapy, for example pharmacotherapy, exercisetherapy for strengthening such as back and abdominal muscles,thermotherapy therapy such as hot pack, acupuncture therapy forrelieving pain, orthotic therapy such as corset and the like in mildcase. However, there is no therapy for various symptoms of spinal canalstenosis to improve satisfactorily.

Many of spinal canal stenosis patients are treated with conservativetherapy and many of them improve their condition by combination ofconservative therapies. However, oral prostaglandin E1 derivatives forthe improvement of the circulation in the nerve tissue, are the onlylaunched drug for spinal canal stenosis. Therefore, the presentinventors have made extensive studies to find a therapeutic agent forspinal canal stenosis, and as a result, have found that an aldosereductase inhibitor is unexpectedly able to improve the condition ofspinal canal stenosis, and then have completed the present invention. Ithas not been reported that the aldose reductase inhibitors are effectivefor the treatment of spinal canal stenosis. These inventors confirmedfor the first time that the aldose reductase inhibitors were effectivefor the treatment of the spinal canal stenosis by using a rat of gaitdisturbance model by cauda equina compression (J. Neurosci. Methods,104(2), 191-198 (2002)) known as a model with the spinal canal stenosis.

Namely, the present invention relates to the followings:

1. a preventive and/or therapeutic agent for spinal canal stenosis,which comprises an aldose reductase inhibitory compound,

2. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the spinal canal stenosis is cervicalspinal canal stenosis, thoracic spinal canal stenosis, lumbar spinalcanal stenosis or wide spinal canal stenosis,

3. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the agent is used for improvingparalysis, hypoesthesia, pain or numbness,

4. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the agent is used for improvingphysical ability,

5. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 4, wherein the agent for improving physicalability is used for improving reduction of muscle power, intermittentclaudication and gait disability,

6. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the agent is used for improvingdysuria or dyschezia,

7. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the aldose reductase inhibitorycompound is represented by formula (I) wherein all groups are the samemeaning as described hereinafter, a salt when R^(3a) is hydrogen, or asolvate thereof,

8. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein the aldose reductase inhibitorycompound is a compound represented by formula (II), wherein thedefinition of each group is the same meaning as hereinafter, a saltthereof or a solvate thereof, a compound represented by formula (III),wherein the definition of each group is the same meaning as hereinafter;a salt thereof or a solvate thereof, or a compound represented byformula (IV), wherein definition of each group is the same meaning ashereinafter, a salt thereof or a solvate thereof,

9. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 7, wherein the aldose reductase inhibitorycompound is5-[(1Z,2E)-2-methylphenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid,

10. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 8, wherein the aldose reductase inhibitorycompound is(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidine]-1,2′,3,5′-tetrone,(2S,4S)-6-fluoro-2′,5′-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4′-imidazolidine]-2-carboxamideor2-[3-(4-bromo-2-fluorobenzyl)-7-chrolo-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]aceticacid,

11. the preventive and/or therapeutic agent for spinal canal stenosisaccording to the above 1, wherein an aldose reductase inhibitorycompound is

(1) DL-spiro(2-fluoro-9H-fluoren-9,4′-imidazolidine)-2′,5′-dione,

(2)2,7-difluoro-4,5-dimethoxyspiro[9H-fluoren-9,4′-imidazolidine]-2′,5′-dione,

(3)N-[3,5-dimethyl-4-(nitromethylsulphonyl)phenyl]-2-(2-methylphenyl)acetamide,

(4) N-(carboxymethyl)-7-fluoro-N-methyl-9-oxoxanthin-2-sulphoamide,

(5) 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydrofuran-2-yl)propanoic acidethyl ester,

(6)2-formamide-3-[5′-(2-formamide-1-hydroxyethyl)-2,2′-dihydroxybiphenyl-5-yl]-3-hydroxypropyonicacid,

(7) 2-[3-methyl-5-(4,5,7-trifluorobenzothiazol-2-ylmethyl)phenyl]aceticacid,

(8) 2-[5-fluoro-2-[N-(3-nitrobenzyl)thiocarbamoyl]phenoxyacetic acid,

(9)8′-chrolo-2′,3′-dihydrospiro[pyrrolidine-(3,6′)(5′H)-pyrro-[1,2,3-de][1,4]benzoxazine]-2,5,5′-trione,

(10)2-[1-(3,4-dichrolobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]aceticacid,

(11)2-[4-(4,5,7-trifluoro-benzothiazol-2-yl)methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid,

(12) 1-(benzo[b]thiophen-2-ylsulphonyl)hydantoin,

(13) 1-(3-bromobenzo[b]furan-2-ylsulphonyl)hydanthione,

(14) 3-(carboxymethyl)-1-(3-nitrobenzyl)parabanic acid,

(15)1′,3′-bis(acetoxymethyl)spiro[fluoren-9,4′-imidazolidine]-2′,5′-dione,

(16) 2,8-diisopropyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazine-4-aceticacid,

(17)N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine),

(18) (2,6-dimethylphenylsulphonyl)nitromethane,

(19)N-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenyl]-1-phenyl-cyclopropane-1-carboxamide,

(20)2-[3-oxo-4-(4,5,7-trifluorobenzothiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid,

(21)2-[3,7-dimethylocta-2(E),6-dienyl]-2,3-epoxy-5,7-dihydroxy-6-methyl-1,2,3,4-tetrahydronaphthalene-1,4-dione,(22) 6-fluoro-2-methylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione,

(23) (S)-6-fluorospiro(chroman-4,4′-imidazolidine)-2′,5′-dione,

(24)3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid,

(25) 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione,

(26) 3-[(4-bromo-2-fluorophenyl)methyl]-3,4-dihydro-4-oxo-1-phthalazineacetic acid,

(27) ascorbyl gamolenate,

(28) ICI-10552,

(29) ICI-215918,

(30) JTT-811,

(31) lindolrestat,

(32) salfredins,

(33) TJN-732,

(34) TAT,

(35) thiazocin-A,

(36) axillarin, or

(37) minalrestat,

12. a medicine which comprises aldose reductase inhibitory compoundsaccording to the above 1 in combination with at least one pharmaceuticalagent selected from aldose reductase inhibitory compounds according tothe above 1, prostaglandins, prostaglandin derivatives formulations,nonsteroidal anti-inflammatory drugs, vitamin compounds, musclerelaxants, antidepressants, poly ADP-ribose polymerase inhibitors,excitatory amino acid receptor antagonists, radical scavengers,astrocyte modulators, IL-8 receptor antagonists, and immunosuppressivedrugs,

13. a method for prevention and/or treatment for spinal canal stenosis,which comprises administering to a mammal an effective amount of analdose reductase inhibitory compound, and

14. use of an aldose reductase inhibitory compound for preparation of apreventive and/or therapeutic agent for spinal canal stenosis.

The aldose reductase inhibitory compounds of the present inventioninclude all of the agents which have aldose inhibitory activity. Inaddition, the aldose reductase inhibitory compounds not only which hasbeen found up to now but also which will be found in future areincluded.

The aldose reductase inhibitory compounds include epalrestat (U.S. Pat.No. 4,464,382), fidarestat (SNK-860; U.S. Pat. No. 4,740,517),(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidine]-1,2′,3,5′-tetrone(AS-3201; JP-A-5-186472), zenarestat (FK-366; U.S. Pat. No. 4,734,419and U.S. Pat. No. 4,883,800),DL-spiro(2-fluoro-9H-fluoren-9,4′-imidazolidine)-2′,5′-dione (imirestat,AL-1567; JP-A-60-89469),2,7-difluoro-4,5-dimethoxyspiro[9H-fluoren-9,4′-imidazolidine]-2′,5′-dione(AL-4114; JP-A-60-89469),N-[3,5-dimethyl-4-(nitromethylsulfonyl)phenyl]-2-(2-methylphenyl)acetamide(ZD-5522),N-(carboxymethyl)-7-fluoro-N-methyl-9-oxoxanthine-2-sulfoamide(BAL-ARI8; EP307879),3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydrofuran-2-yl)-propanoic acid ethylester (FR-62765; EP189272),2-formamide-3-[5′-(2-formamide-1-hydroxyethyl)-2,2′-dihydrooxybiphenyl-5-yl]-3-hydroxypropionicacid (WF-2421(FR-90028); JP-A-2-72144),2-[3-methyl-5-(4,5,7-trifluorobenzothiazol-2-ylmethyl)-phenyl]aceticacid (GP-1447; EP714893),2-[5-fluoro-2-[N-(3-nitrobenzyl)thiocarbamoyl]phenoxy]acetic acid(IDD-598),8′-chrolo-2′,3′-dihydrospiro-[pyrrolidine-(3,6′)(5′H)-pyrrolo[1.2.3-de][1,4]benzoxazine]-2,5,5′-trione(ADN-138),2-[1-(3,4-dichrolobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]aceticacid (ADN-311),2-[4-(4,5,7-trifluorobenzo-thiazol-2-yl)methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid (SG-210), 1-(benzo[b]thiophen-2-ylsulfonyl)hydantoin (M-16049;EP355827)), 1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydanthion (M-16209;EP355827), 3-(carboxymethyl)-1-(3-nitrobenzyl)parabanic acid (NZ-314;EP353198),1′,3′-bis(acetoxymethyl)spiro[fluoren-9,4′-imidazolidine]-2′,5′-dione(CP-AR-3192; U.S. Pat. No. 4,853,401),2,8-diisopropyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazine-4-acetic acid(AD-5467; EP243018),N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine(tolrestat; U.S. Pat. No. 4,439,617),(2,6-dimethylphenylsulfonyl)nitromethane (ICI-215918),N-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenyl]-1-phenyl-cyclopropane-1-carboxyamide(DN-108; WO97/32863),2-[3-oxo-4-(4,5,7-trifluorobenzothiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid (SPR-210; EP492667),2-[3,7-dimethylocta-2(E),6-dienyl]-2,3-epoxy-5,7-dihydroxy-6-methyl-1,2,3,4-tetrahydronaphthalene-1,4-dione(A-74863a; JP-A-7-10857), ICI-10552, ICI-215918,6-fluoro-2-methylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione(methosorbinil; JTT-811), lindolrestat (IDD-676; WO99/50268),(S)-6-fluorospiro(chroman-4,4′-imidazolidine)-2′,5′-dione (sorbinil;U.S. Pat. No. 4,474,967),3,4-dihydro-4-oxo-3-[[5-((trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid (zopolrestat; EP222576), ascorbyl gamolenate (SC-103,CA2143603), 5-(3-ethoxy-4-(pentyloxyphenyl)-2,4-thiazolidinedione(risarestat, CT-112; EP33617), salfredins (TJN-732, TAT(EP421365)),thiazocin-A, axillarin,3-[(4-bromo-2-fluorophenyl)methyl]-3,4-dihydro-4-oxo-1-phthalazineacetic acid (ponalrestat; EP2895), minalrestat (WAY-121509; EP365324)and the like.

In addition, the compound with aldose reductase inhibitory activity,described in the specification of U.S. Pat. No. 4,464,382, U.S. Pat. No.4,740,517, JP-A-5-186472, JP-A-5-345784, U.S. Pat. No. 4,734,419, U.S.Pat. No. 4,883,800, JP-A-60-89469, EP307879, EP189272, JP-A-2-72144,EP714893, WO99/50268, EP355827, EP355827, EP353198, U.S. Pat. No.4,474,967, EP222576, U.S. Pat. No. 4,853,401, CA2143603, EP33617,EP243018, EP421365, U.S. Pat. No. 4,439,617, EP2895, EP365324,WO97/32863, EP492667, JP-A-7-10857, EP1236720, EP1236720, WO92/17446,JP-A-2002-241347, EP269355, JP-A-62-67075, EP252713, EP305947, EP322255,WO98/28265, EP17379, WO89/09773 and the like are useful. Therefore, thepresent invention includes the application for these compounds to use ofthe present invention.

Among the compounds of the present invention, a preferred compoundincludes the compound represented by formula (I):

wherein

1) R^(1a) and R^(2a) are the same or different and each representsphenyl which may be substituted by at least one group selected from thefollowing (1)-(10):

(1) halogen,

(2) trifluoromethyl,

(3) hydroxyl,

(4) nitro,

(5) carboxyl,

(6) amino which may be substituted by C1-4 alkyl,

(7) C1-4 alkyl, alkoxy or alkylthio,

(8) phenyl,

(9) a heterocyclic group containing at least one atom selected from anitrogen atom, a sulfur atom and an oxygen atom, which may besubstituted by at least one group selected from (a) halogen, (b)trifluoromethyl, (c) phenyl, (d) nitro, (e) hydroxyl, (f) carboxyl, (g)amino which may be substituted by C1-4 alkyl, (h) C1-4 alkyl, (j) C1-4alkoxy, and (k) C1-4 alkylthio, or

(10) C1-4 alkyl which may be substituted by at least one substituentselected from hydroxyl, phenyl, and a heterocyclic group selected fromdescribed above (9),

2) R^(1a) is hydrogen and R^(2a) is the following (1)-(6):

(1) C4-7 cycloalkyl or cycloalkenyl which may be substituted by at leastone C1-4 alkyl,

(2) anthryl or naphthyl,

(3) phenyl which may be substituted by at least one group selected fromthe following (a)-(k):

-   -   (a) halogen,    -   (b) trifluoromethyl,    -   (c) hydroxyl,    -   (d) nitro,    -   (e) carboxyl,    -   (f) amino which may be substituted by C1-4 alkyl    -   (g) C1-4 alkyl, alkoxy or alkylthio,    -   (h) phenyl,    -   (j) a heterocyclic group containing at least one atom selected        from a nitrogen atom, a sulfur atom and an oxygen atom, which        may be substituted by at least one group selected from (i)        halogen, (ii) trifluoromethyl, (iii) phenyl, (iv) nitro, (v)        hydroxyl, (vi) carboxyl, (vii) amino which may be substituted by        C1-4 alkyl, (viii) C1-4 alkyl, (ix) C1-4 alkoxy, and (x) C1-4        alkylthio,    -   (k) C1-4 alkyl which is substituted by at least one group        selected from hydroxyl, phenyl, and the heterocyclic group        described above (j),

(4) a heterocyclic group containing at least one atom selected from anitrogen atom, a sulfur atom and an oxygen atom, which may besubstituted by at least one group selected from the following (a)-(k):

-   -   (a) halogen,    -   (b) trifluoromethyl,    -   (c) phenyl,    -   (d) nitro,    -   (e) hydroxyl,    -   (f) carboxyl,    -   (g) amino which may be substituted by C1-4 alkyl,    -   (h) C1-4 alkyl, alkoxy or alkylthio,    -   (j) oxo, or    -   (k) C1-4 alkyl substituted by at least one substituent selected        from hydroxyl, phenyl, and the heterocyclic group described        above (j) in (3),

wherein R^(4a) is hydrogen or C1-4 alkyl, or

3) R^(1a) taken together with R^(2a) is tetramethylene or pentamethlene;

R^(3a) is

(1) hydrogen,

(2) C1-12 alkyl,

(3) C7-13 aralkyl,

(4) C4-7 cycloalkyl or cycloalkenyl which may be substituted by at leastone C1-4 alkyl,

(5) phenyl which may be substituted by at least one group selected fromthe following (a)-(k):

-   -   (a) halogen,    -   (b) trifluoromethyl,    -   (c) hydroxyl,    -   (d) nitro,    -   (e) carboxyl,    -   (f) amino which may be substituted by C1-4 alkyl,    -   (g) alkoxy or alkythio which may be substituted by C1-4 alkyl,    -   (h) phenyl,    -   (j) a heterocyclic group containing at least one atom selected        from a nitrogen atom, a sulfur atom and an oxygen atom, which        may be substituted by at least one group selected from (i)        halogen, (ii) trifluoromethyl, (iii) phenyl, (iv) nitro, (v)        hydroxyl, (vi) carboxyl, (vii) amino which may be substituted by        C1-4 alkyl, (viii) C1-4 alkyl, (ix) C1-4 alkoxy, and (x) C1-4        alkylthio, and,    -   (k) C1-4 alkyl substituted by at least one substituent selected        from hydroxyl, phenyl, and the heterocyclic group described        above (j), or a salt of acid thereof when R^(3a) represents        hydrogen, or a solvate thereof In the definition of formula (I),

C1-4 alkyl is methyl, ethyl, propyl, butyl, or isomers thereof,

C1-4 alkoxy is methoxy, ethoxy, propoxy, butoxy or isomers thereof,

C1-4 alkylthio is methylthio, ethylthio, propylthio, butylthio, orisomers thereof,

C4-7 cycloalkyl is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orisomers thereof,

C4-7 cycloalkenyl is cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl or isomers thereof, and

C1-12 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl or isomers thereof

In addition, a preferred compound includes a compound represented byformula (II):

wherein R^(1b) represents (1) hydrogen, (2) lower alkyl, (3) substitutedor unsubstituted aryl(lower alkyl), (4) substituted or unsubstitutedaryl, or (5)

wherein R^(4b) and R^(5b) are the same or different and each represents(a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) lower alkyl, (e)lower alkoxy, (f) acyl, (g) nitro, (h) amino, (i) lower alkylamino, or(j) di(lower alkyl)amino; U^(b) represents (a) oxygen, (b) sulfur, or(c) —NR^(6b)—wherein NR^(6b) represents hydrogen or lower alkyl, andV^(b) represents lower alkyl;

wherein R^(2b) and R^(3b) are the same or different and each represents(1) hydrogen, (2) halogen, (3) lower alkyl, (4) lower alkoxy, (5) acyl,(6) nitro, (7) amino, (8) lower alkylamino, (9) di(lower alkyl)amino,(10) allyl or (11) allyl which is substituted by lower alkyl, loweralkoxy or acyl, or

a salt thereof, or a solvate thereof,

a compound represented by formula (III):

wherein T^(c) represents sulfur or NH;

U^(c) represents oxygen, sulfur or imino;

one of V^(c) and W^(c) represents hydrogen; halogenomethyl;1H-tetrozol-5-yl; —COOR^(c) wherein R^(c) is hydrogen, alkyl,—(CH₂CH₂O)_(n)CH₃ wherein n is an integer of 1 to 113, or substitutedphenyl;

wherein R^(1c) and R^(2c) are the same or different and each representshydrogen, alkyl, —(CH₂CH₂O)_(n)CH₃ wherein n is an integer of 1 to 113,or substituted phenyl; —CH₂OR^(3c) wherein R^(3c) is hydrogen or alkyl;or

wherein R^(4c) and R^(5c) are the same or different and each representshydrogen or alkyl, and the other represents hydrogen or alkyl;

X^(c) represents oxygen or sulfur;

Y^(c) and Z^(c) are the same or different and each represents hydrogen,halogen, alkyl, alkoxy, or alkylthio, or

a salt thereof or a solvate thereof, and

a quinazoline derivative represented by formula (IV):

wherein R^(1d) and R^(2d) are the same or different and each representshydrogen, halogen, lower alkoxy, or halo(lower alkyl);

R^(3d) represents (1) aryl or aryl(lower alkyl) which may besubstituted, or (2) heterocyclic ring-(lower alkyl);

R^(4d) represents carboxy or protected carboxy;

A^(d) represents oxygen or sulfur;

Y^(d) represents carbonyl, thiocarbonyl, or sulfonyl;

Z^(d) represents lower alkylene, or

a salt thereof or a solvate thereof

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-, β- or a mixture thereof, symbol

indicates that it is a mixture of α-configuration and β-configuration,symbol

indicates a single bond or double bond, symbol

indicates a double bond or triple bond, and symbol

indicates a single bond, double bond, or triple bond.

Furthermore, among the compounds of the present invention, a morepreferred compound is

5-[(1Z,2E)-2-methylphenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (epalrestat) included in formula (I),

(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidin]-1,2′,3,5′-tetrone(AS-3201) included in formula (II),

(2S,4S)-6-fluoro-2′,5′-diioxospiro[3,4-dihydro-2H-1-benzopyran-4,4′-imidazolidine-2-carboxamide(SNK-860; fidarestat) included in formula (III), or

2-[3-(4-bromo-2-fluorobenzyl)-7-chrolo-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]aceticacid (FK-366; zenarestat) included in formula (IV).

The compound of the present invention may be converted into salts by aknown method.

In the specification, salts include salts of alkali metals, salts ofalkaline earth metals, ammonium salts, salts with organic amines, acidaddition salts and the like.

The salts are preferably non-toxic and water-soluble. Suitable saltsinclude, for example, salts of alkali metals (potassium or sodium,etc.), salts of alkaline earth metals (calcium or magnesium, etc.),ammonium salts, pharmacologically acceptable salts with organic amines(tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine or N-methyl-D-glucamine, etc.).

The acid addition salts are preferably non-toxic and water-soluble.Suitable acid addition salts include salts of inorganic acids(hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate,etc.), salts of organic acids (acetate, trifluoroacetate, lactate,tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,isethionate, glucuronate, gluconate, etc.), and the like.

The compound of the present invention and salts thereof may be convertedinto non-toxic and pharmaceutically acceptable solvates by a knownmethod.

The solvates are preferably non-toxic and water-soluble. Suitablesolvates include water, alcohol solvents (ethanol, etc.), and the like.

Unless otherwise specified, the present invention includes all isomers.For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene,alkenylene, alkynylene, etc. include straight or branched ones. Inaddition, the present invention also include isomers on double bond,ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atoms (R-, S-isomer, α-, β-configuration, enantiomer,diastereomer), optically active isomers (D-, L-, d-, l-isomer), polarcompounds generated by chromatogaphic separation (more polar compound,less polar compound), equilibrium compounds, rotational isomers,mixtures thereof at any ratios and racemic mixtures.

Processes for the Preparation of the Compound of the Present Invention:

The compound represented by formula (I) may be prepared by methodsdescribed in U.S. Pat. No. 4,464,382, the compound represented byformula (II) may be prepared by methods described in JP-A-5-186472 andJP-A-5-345784, the compound represented by formula (III) may be preparedby methods described in U.S. Pat. No. 4,740,517 and the compoundrepresented by formula (IV) may be prepared by methods described in U.S.Pat. No. 4,734,419 and U.S. Pat. No. 4,883,800.

Furthermore, the compound used in the present invention may be preparedby the method described in U.S. Pat. No. 4,883,800, EP218999,JP-A-60-89469, EP307879, EP189272, JP-A-2-72144, EP714893, WO99/50268,EP355827, EP355827, EP353198, U.S. Pat. No. 4,474,967, EP222576, U.S.Pat. No. 4,853,401, CA2143603, EP33617, EP243018, EP421365, U.S. Pat.No. 4,439,617, EP2895, EP365324, WO97/32863, EP492667, JP-A-7-10857,EP1236720, EP1236720, WO92/17446, JP-A-2002-241347, EP269355,JP-A-62-67075, EP252713, EP305947, EP322255, WO98/28265, EP17379, orWO89/09773.

Pharmacological Activities:

The compound in the present invention is efficacious in a gaitdisturbance model of cauda equina compression, known as a spiral canalstenosis model. Therefore, aldose reductase inhibitory compounds areuseful for spinal canal stenosis, and can improve motor function,especially muscle weakness, muscle weakness, and decreasing in walkingability of spinal canal stenosis patients. Furthermore, the compound isuseful for paralysis, hypoesthesia, pain, or numbness of patients,especially lower limb paralysis, hypoesthesia, pain or numbness. Inaddition, it is effective in the therapy for bladder or rectum disorderdue to spinal canal stenosis. Bladder disorder due to spinal canalstenosis means dysuria due to it. It includes frequent miction, delayedurination, forceless urinary stream, ischuria and urinary incontinence.Furthermore, rectal disorder due to spinal canal stenosis meansdefecation disorder due to it.

The effect of therapy for spiral canal stenosis by the compound in thepresent invention is thought to be based on the improvement ofhypofunction of the surrounding tissue of spinal canal, for exampleintervertebral disk, or the improvement of hyperplasia of yellowligament, posterior ligament or the like, the improvement ofinflammation or reduction of blood flow due to nerve compression, or thenerve protection.

Toxicity:

The toxicity of the compound of the present invention is very low, andit is confirmed that the compound is safe enough for pharmaceutical use.For example, in the case of oral administration of epalrestat to rat,LD₅₀ is 5600 mg/kg.

Application to Pharmaceuticals:

A combination agent obtained by combining the compound of formula (I) ora non-toxic salt thereof with other medicaments may be administered toaccomplish the following purposes:

1) to supplement and/or enhance the preventive and/or therapeutic effectof the present compound;

2) to improve the kinetics and/or absorption and reduce the dose of thepresent compound; and/or

3) to eliminate the side effects of the present compound; and

A combination of the compound of the present invention and othermedicaments may be administered in the form of the formulations havingthese components incorporated in one preparation, or may be administeredin separate preparations. In the case where these medicaments areadministered in separate preparations, they may be administeredsimultaneously or at different times. In the latter case, the compoundof the present invention may be administered before the othermedicaments. Alternatively, the other medicaments may be administeredbefore the compound of the present invention. The method for theadministration of these medicaments are the same or different.

The diseases on which the preventive and/or therapeutic effect of theabove mentioned combination preparations works are not specificallylimited but may be those for which the preventive and/or therapeuticeffect of the compound of the present invention is supplemented and/orenhanced.

The other pharmaceutical for supplementing and/or enhancing theprevention and/or treatment effect of the compound of the presentinvention for spiral canal stenosis includes, for exampleprostaglandins, prostaglandin derivatives, nonsteroidalanti-inflammatory drug (NSAID), vitamin, muscle relaxant,anti-depressant, poly ADP-ribose polymerase (PARP) inhibitor, excitatoryamino acid receptor antagonist (such as NMDA receptor antagonist andAMPA receptor antagonist), radical scavenger, astrocyte modulatingagent, IL-8 receptor antagonist, immunosuppressive drug (such as FK506and cyclosporine).

Examples of prostaglandins (hereinafter, abbreviated as PG) include PGreceptor agonists, PG receptor antagonists, and the like.

Examples of PG receptors include PGE receptors (EP1, EP2, EP3 and EP4),PGD receptors (DP, CRTH2), PGF receptors (FP), PGI receptors (IP), TXreceptors (TP), and the like. In addition, examples of prostaglandinderivative formulations include limaprost, limaprost alfadex, beraprostand the like.

Examples of NSAID include sasapyrine, sodium salicylate, aspirin,aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate,dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetinsodium, clinoril, fenbufen, nabumetone, proglumetacin, indomethacinfarnesyl, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac,etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen,flurbiprofen axetil, ketoprofen, Fenoprofen calcium salt, tiaprofenicacid, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen,zaltoprofen, mefenamic acid, mefenamic acid aluminium, tolfenamic acid,floctafenine, ketophenylbutazone, oxiphenbutazone, piroxicam, tenoxicam,ampiroxicam, napageln ointment, epirizole, tiaramide hydrochloride,tinoridine hydrochloride, emorfazone, sulpvrine, migrenin, Saridon,Sedes G, amipylo-N, solvon, pyrine compounding cold medicine,acetaminophen, phenacetin, dimetotiazine mesilate, cimetoride-combineddrug, non-pyrine-combined cold medicine and the like.

Examples of muscle relaxant include tolperisone hydrochloride,chlorzoxazone, chlormezanone, methocarbamol, phenprobamate, pridinolmesilate, chlorphenesin carbamate, baclofen, eperisone hydrochloride,afloqualone, tizaindine hydrochloride, alcuronium chloride,suxamethonium chloride, tubocurarine chloride, dantrolene sodium,pancuronium bromide, vecuronium bromide and the like.

Examples of tricyclic antidepressant include imipramine hydrochloride,desipramine hydrochloride, clomipramine hydrochloride, trimipraminemaleate, amitriptyline hydrochloride, nortriptyline hydrochloride,lofepramine hydrochloride, amoxapine, dosulepin hydrochloride and thelike.

Examples of tetracyclic antidepressant include maprotiline, mianserinand the like.

The weight ratio of the compound of the present invention and the othermedicaments is not specifically limited.

The other medicaments may be administered as a combination of same ordifferent kind of more than two arbitrary medicants.

Furthermore, the other medicaments for supplementing and/or enhancingthe preventive and/or therapeutic effect of the present inventioninclude not only those found so far but also those which will be foundon the basis of the above mentioned mechanism.

The compounds of the present invention naturally include all saltsprepared by known methods. The pharmacologically acceptable salts arepreferable. It is confirmed that all the compounds described in theSpecification and the Claims have pharmacologically acceptablelow-toxicity and safe enough for pharmaceutical use.

The pharmacologically acceptable salts described in the presentinvention are for example, alkaline metal, alkaline earth metal,ammonium salt or salt with amine when a parent compound is an acidiccompound, and for example organic or inorganic acid addition salt when aparent compound is a basic compound.

In addition, the compound of the present invention may be administratedthe following acid addition salt thereof. The acid addition salts arepreferably non-toxic and water-soluble. The appropriate acid additionsalts include, for example, salts of inorganic acids (hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), salts oforganic acids (acetate, trifluoroacetate, lactate, tartrate, oxalate,fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate,etc.) and the like. Hydrochloride is preferable as an acid additionsalt.

Furthermore, the compounds used in the present invention or saltsthereof may be solvates thereof

The solvates are preferably non-toxic and water-soluble. The appropriatesolvates include, for example, solvates such as water, alcohol solvents(ethanol, etc.), and the like.

In addition, the compounds used in the present invention may be prodrugsprepared by a known method.

The prodrug for the compound of the present invention means a compoundwhich is converted into the compound of the present invention byreaction with an enzyme, a gastric acid, or the like, in the livingbody. Examples of the prodrug for the compound of the present inventioninclude a compound wherein hydroxyl of the compound of the presentinvention is substituted with acyl, alkyl, phosphoric acid, boric acid,or the like (e.g., a compound wherein hydroxyl of the compound of thepresent invention is modified with acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.);a compound wherein carboxyl of the compound of the present invention ismodified with ester, amide, or the like (e.g., a compound whereincarboxyl of the compound of the present invention is modified with ethylester, phenyl ester, carboxymethyl ester, dimethyl aminomethyl ester,pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide, etc.); and the like. Inaddition, the prodrug for the compound of the present invention mayhydrate or non-hydrate.

The compound of the present invention and ester thereof may be convertedinto α-, β-, or γ-cyclodextrin, or cyclodextrin clathrate compound usingα-, β-, or γ-cyclodextrin by the method described in GB1351238 orGB1419221. It is convenient for the use of drug because it increases itsstability and its water solubility by converting into cyclodextrinclathrate.

For the purpose above described, the compound used in the presentinvention, or a combination of the present invention compound and othermedicaments may be normally administered systemically or locally,usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,ages, body weights, symptoms, the desired therapeutic effects, the routeof administration and the duration of the treatment. For the humanadult, the doses per person are generally from 0.1 ng to 100 mg, by oraladministration, up to several times per day, and from 0.1 ng to 10 mg,by parenteral administration (preferably intravenous injection), up toseveral times per day, or continuous administration 1 to 24 hours perday from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

To administer the compounds in the present invention, use is made ofsolid preparations for internal use and liquid preparations for internaluse for oral administration as well as preparations for injections,external preparations, suppositories, eye drops, inhalations and thelike for parenteral administration.

Examples of the solid preparations for internal use for oraladministration include tablets, pills, capsules, powders, granules andthe like. The capsules include hard capsules and soft capsules. Thetablets include sublingual tablets, intraoral patches, orally fastdisintegrating tablets and the like.

Such a solid preparation for internal use is prepared by a formulationmethod commonly employed by using one or two or more active substanceseither as it is or as a mixture with an excipient (lactose, mannitol,glucose, microcrystalline cellulose, starch, etc.), a binder(hydroxypropylcellulose, polyvinylpyrrolidone, magnesium metasilicatealuminate, etc.), a disintegrating agent (calcium cellulose glycolate,etc.), a lubricant (magnesium stearate, etc.), a stabilizer and adissolution aid (glutamic acid, aspartic acid, etc.). If necessary, itmay be coated with a coating agent (sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.).It may be coated with two or more layers. Moreover, capsules made of anabsorbable material such as gelatin are involved in the scope thereof.

The sublingual tablets may be prepared in accordance with a well knownmethod. For example, a sublingual tablet is prepared by a formulationmethod commonly employed by using one or more active substances are usedmixed with an excipient (lactose, mannitol, glucose, microcrystallinecellulose, starch, etc.), a binder (hydroxypropylcellulose,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.), adisintegrator (starch, L-hydroxypropyl cellulose, carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, etc.), alubricant (magnesium stearate, etc.), a swelling agent (hydroxypropylcellulose, hydroxylpropylmethy cellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), a swellingaid agent (glucose, fructose, mannitol, xylitol, erythritol, maltose,trehalose, phosphate, citrate, silicate, glycine, glutamic acid,arginine, etc.), a stabilizer and a dissolution aid (polyethyleneglycol, propylene glycol, glutamic acid, aspartic acid, etc.), aflavoring agent (orange, strawberry, mint, lemon, vanilla, etc.). Ifnecessary, it may be coated with a coating agent (sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.).If necessary, it may be coated with two or more layers. Moreover, it mayalso further comprise some additives such as sweetening agents,antioxidants, coloring agents, preservatives and the like.

The intraoral patch may be prepared in accordance with a well knownmethod. For example, a intraoral patch is prepared by a formulationmethod commonly employed by using one or more active substances are usedmixed with an excipient (lactose, mannitol, glucose, microcrystallinecellulose, starch, etc.), a binder (hydroxypropylcellulose,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.), adisintegrator (starch, L-hydroxypropyl cellulose, carboxymethylcellulose, croscarmellose sodium, calcium cellulose glycolate, etc.), alubricant (magnesium stearate, etc.), a attach agent (hydroxypropylcellulose, hydroxylpropylmethy cellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), a attach aidagent (glucose, fructose, mannitol, xylitol, erythritol, maltose,trehalose, phosphate, citrate, silicate, glycine, glutamic acid,arginine, etc.), a stabilizer and a dissolution aid (polyethyleneglycol, propylene glycol, glutamic acid, aspartic acid, etc.), aflavoring agent (orange, strawberry, mint, lemon, vanilla, etc.) and thelike. If necessary, it may be coated with a coating agent (sucrose,gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,etc.) and the like. If necessary, it may be coated with two or morelayers. Moreover, it may also further comprise some additives such assweetening agents, antioxidants, coloring agents, preservatives and thelike.

The orally fast disintegrating tablets may be prepared in accordancewith a well known method. For example, an orally fast disintegratingtablets is prepared by a formulation method commonly employed by usingone or more active substances either as it is, or as a mixture bulk orgranulated bulk materials which is coated with an adequate coating agent(ethyl cellulose, hydroxypropyl cellulose, hydroxylpropylmethycellulose, acrylate-methacrylate-copolymer, etc.), a plasticizer(polyethylene glycol, triethyl citrate, etc.), with an excipient(lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.),a binder (hydroxypropylcellulose, polyvinylpyrrolidone, magnesiummetasilicate aluminate, etc.), a disintegrator (starch, L-hydroxypropylcellulose, carboxymethyl cellulose, croscarmellose sodium, calciumcellulose glycolate, etc.), a lubricant (magnesium stearate, etc.), adispersion aid (glucose, fructose, mannitol, xylitol, erythritol,maltose, trehalose, phosphate, citrate, silicate, glycine, glutamicacid, arginine, etc.), a stabilizer and a dissolution aid (polyethyleneglycol, propylene glycol, glutamic acid, aspartic acid, etc.), aflavoring agent (orange, strawberry, mint, lemon, vanilla, etc.) and thelike. If necessary, it may be coated with a coating agent (sucrose,gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,etc.) and the like. If necessary, it may be coated with two or morelayers. Moreover, it may also further comprise some additives such assweetening agents, antioxidants, coloring agents, preservatives and thelike.

The liquid preparations for internal use for oral administration includepharmaceutically acceptable aqueous solutions, suspensions, emulsions,syrups, elixirs and the like. Such a liquid preparation is prepared bydissolving, suspending or emulsifying one or more active substances in adiluent commonly employed (purified water, ethanol or a mixture thereof,etc.). Such liquid forms may also further comprise some additives suchas humectants, suspending agents, emulsifying agents, sweetening agents,flavoring agents, aroma, preservatives, buffers and the like.

The dosage forms of the parenteral administration preparations forexternal use include ointments, gels, creams, fomentations, patches,liniments, atomized agents, inhalations, sprays, aerosols, eye drops,nasal drops and the like. Such a preparation contains one or more activesubstances and is prepared by a well known method or a commonly employedformulation.

Ointments are prepared in accordance with a well known formulation or acommonly employed formulation. For example, they are prepared bysoftening or melting one or two or more active substances in a base. Theointment base is selected from well known ones or those commonlyemployed. For example, use may be made of one base or a mixture of twoor more thereof selected from higher fatty acids or higher fatty acidesters (adipic acid, myristic acid, palmitic acid, stearic acid, oleicacid, adipic acid esters, myristic acid esters, palmitic acid esters,stearic acid esters, oleic acid esters, etc.), waxes (beeswax, whalewax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphoricacid esters, etc.), higher alcohols (cetanol, stearyl alcohol,cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.),hydrocarbons (hydrophilic vaseline, white vaseline, refined lanolin,liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol,propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils(castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils(mink oil, yolk oil, squalane, squalene, etc.), water, absorptionpromoters and skin irritation inhibitors. The ointments may furthercontain a humectant, a preservative, a stabilizer, an antioxidant, aflavor, and the like.

Gels are prepared in accordance with a well known formulation or aformulation commonly employed. For example, they are prepared by meltingone or more active substances in a base. The gel base is selected fromwell known ones or those commonly employed. For example, use may be madeof one base or a mixture of two or more thereof selected from loweralcohols (ethanol, isopropyl alcohol, etc.), gelling agents(carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,ethylcellulose, etc.), neutralizing agents (triethanolamine,diisopropanolamine, etc.), surfactants (polyethylene glycolmonostearate, etc.), gums, water, absorption promoters and skinirritation inhibitors. The gels may further contain a preservative, anantioxidant, a flavor, and the like.

Creams are prepared in accordance with a well known formulation or aformulation commonly employed. For example, they are prepared by meltingor emulsifying one or more active substances in a base. The cream baseis selected from well known ones or those commonly employed. Forexample, use may be made of one base or a mixture of two or more thereofselected from higher fatty acid esters, lower alcohols, hydrocarbons,polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.),higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers(polyoxyethylene alkyl ethers, fatty acid esters, etc.), water,absorption promoters and skin irritation inhibitors. The creams mayfurther contain a preservative, an antioxidant, a flavor, and the like.

Fomentations are prepared in accordance with a well known formulation ora formulation commonly employed. For example, they are prepared bymelting one or more active substances in a base, kneading and thenapplying and spreading the kneaded matter on a substrate. Thefomentation base is selected from well known ones or those commonlyemployed. For example, use may be made of one base or a mixture of twoor more thereof selected from thickeners (polyacrylic acid,polyvinylpyrrolidone, gum acacia, starch, gelatin, methylcellulose,etc.), moistening agents (urea, glycerin, propylene glycol, etc.),fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.), water,dissolution aids, tackifiers and skin irritation inhibitors. Thefomentations may further contain a preservative, an antioxidant, aflavor, and the like.

Patches are prepared in accordance with a well known formulation or aformulation commonly employed. For example, they are prepared by meltingone or more active substances in a base and then applying and spreadingon a substrate. The patch base is selected from well known ones or thosecommonly employed. For example, use may be made of one base or a mixtureof two or more thereof selected from polymer bases, fats and oils,higher fatty acids, tackifiers and skin irritation inhibitors. Thepatches may further contain a preservative, an antioxidant, a flavor,and the like.

Liniments are prepared in accordance with a well known formulation or aformulation commonly employed. For example, they are prepared bydissolving, suspending or emulsifying one or two or more activesubstances in one or more media selected from water, alcohols (ethanol,polyethylene glycol, etc.), higher fatty acids, glycerin, soap,emulsifiers, suspending agents, and the like. The liniments may furthercontain a preservative, an antioxidant, a flavor, and the like.

Atomized agents, inhalations and sprays may contain, in addition, to adiluent commonly employed, a stabilizer such as sodium hydrogen sulfite,a buffering agent for imparting isotonicity, for example, an isotonicagent such as sodium chloride, sodium citrate or citric acid. Methodsfor producing a spray are described in detail in, for example, U.S. Pat.No. 2,868,691 and U.S. Pat. No. 3,095,355.

The injections for parenteral administration include solutions,suspensions, emulsions and solid injections to be dissolved or suspendedbefore use. Such an injection is used by dissolving, suspending oremulsifying one or more active substances in a solvent. The solventincludes, for example, distilled water for injection, physiologicalsaline, vegetable oils, alcohols such as propylene glycol, polyethyleneglycol and ethanol, and mixtures thereof The injection may furthercontain a stabilizer, a dissolution aid (glutamic acid, aspartic acid,Polysorbate 80 (registered trademark), etc.), a suspending agent, anemulsifier, a soothing agent, a buffer, a preservative, and the like.Such an injection may be produced by sterilizing at the final step oremploying an aseptic process. Alternatively, it is also possible that anaseptic solid product such as a freeze-dried product is produced andsterilized or dissolved in aseptic distilled water for injection oranother solvent before use.

The inhalations for parenteral administration include aerosols, powdersfor inhalation and liquids for inhalation. Such inhalations may bedissolved or suspended in water or another adequate medium for use.

The inhalations may be prepared in accordance with a well known method.

For example, liquid preparations for inhalation may be, if necessary,prepared by appropriately selecting a preservative (benzalkoniumchloride, paraben, etc.), a colorant, a buffering agent (sodiumphosphate, sodium acetate, etc.), an isotonic agent (sodium chloride,concentrated glycerin, etc.), a thickener (carboxyvinyl polymer, etc.),an absorption promoter, and the like.

Powders for inhalation may be prepared, if necessary, by appropriatelyselecting a lubricant (stearic acid and its salt, etc.), a binder(starch, dextrin, etc.), an excipient (lactose, cellulose, etc.), acolorant, a preservative (benzalkonium chloride, paraben, etc.), anabsorption promoter, and the like.

When the liquids for inhalation are administered, a sprayer (atomizer,nebulizer) is usually used. When the powders for inhalation are used, aninhalation administration apparatus for powder agents is usually used.

Other compositions for parenteral administration include suppositoriesand pessaries for vaginal administration which contain one or moreactive substances, and are prepared in accordance with commonformulations.

Sustained-release drug may be supplied the compound of the presentinvention directly to affected area continuously. Administration typesof sustained-release drug include implantation and the like.

Examples of biodegenerative polymer used as compositions for prolongeddelivery of therapeutic agents of the present invention includealiphatic acid polyesters or copolymer thereof, polyacrylic acid esters,polyhydroxybutyric acids, polyalkylene oxate, polyorthoesters,polycarbonates, polyamides and the like. These compounds may be usedsingly or in admixture of two or more thereof Examples of the aliphaticacid ester polymers and copolymers thereof include polylactic acid,polyglycolic acid, polycitric acid, polymalic acid, poly-ε-caprolactone,polydioxanone and polyphosphazene. Examples of aliphatic acid polyestersor copolymer thereof include graft, block, alternation and randomcopolymer and two or more thereof. These compounds may be used singly orin admixture of two or more thereof. Besides these compounds,poly-α-cyanoacrylic acid esters, poly-β-hydroxybutyric acids,polytrimethyleneoxates, polyorthoesters, polyorthocarbonates,polyethylene carbonates, poly-γ-benzyl-L-glutamic acids, poly-L-alaninesand copolymer of two or more above described materials may be usedsingly or in admixture of two or more thereof Preferred among thesecompounds are polylactic acids, polyglycolic acids and lacticacid-glycolic acid copolymers, more preferably lactic acid-glycolic acidcopolymers.

Examples of lactic acid used as polylactic acid or lactic acid-glycolicacid copolymer include L-lactic acid, DL-lactic acid and the like.

The average molecular weight of these in vivo degradable polymers to beused in the invention is preferably from about 2,000 to 800,000, morepreferably from about 5,000 to 200,000. For example, the polylactic acidpreferably has a weight-average molecular weight of from about 5,000 to100,000, more preferably from about 6,000 to 50,000. The polylactic acidcan be synthesized according to any known preparation method per se.

In the lactic acid-glycolic acid copolymer, the composition ratio of thelactic acid to the glycolic acid is preferably from about 100/0 to 0/100(w/w), particularly from about 90/10 to 30/70 (w/w). The weight-averagemolecular weight of the lactic acid-glycolic acid copolymer ispreferably from about 5,000 to 100,000, more preferably from about10,000 to 80,000. The lactic acid-glycolic acid copolymer can besynthesized according to any known preparation method per se.

INDUSTRIAL APPLICABILITY

An aldose inhibitory compound is effective for prevention and/ ortherapy for spinal canal stenosis and the like, such as cervical spinalcanal stenosis, thoracic spinal canal stenosis, lumbar spinal canalstenosis and wide spinal canal stenosis and the like. Concretely, it haseffect of improving motor action, especially reduction of muscle power,intermittent claudication and gait disability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that administration of Compound A(5-[(1Z,2E)-2-methylphenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid) is improved the pathology in rats of gait disturbance model bycauda equina compression.

FIG. 2 shows that administration of Compound B((R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidine]-1,2′,3,5′-tetrone)or Compound C((2S,4S)-6-fluoro-2′,5′-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4′-imidazoline]-2-carboxamide)is improved the pathology in rats of gait disturbance model by caudaequina compression.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on Examples andFormulation Examples, but the present invention is not limited thereto.

EXAMPLE 1

Improvement effect of this invented compound in a rat model of gaitdisturbance model by cauda equina compression:

<Method of Making an Animal Model>

A rat of gait disturbance model by cauda equina compression was made bythe method of Takenobu et al. (J. Neurosci. Methods, 104(2), 191-198(2002)). Namely, a rat was anesthetized by sodium pentobarbital, removedits dorsal hair and then was fixed its body in the prone position. Afterdisinfection of the back with Chlorhexidine gluconate (5% HibitenLiquid: Sumitomo Pharmaceuticals), the lumbar was incised along themidline to expose the spine. After excision of the fifth lumbar spinousprocess, silicon rubber 1×4×1.25 mm (height×length×width) were insertedinto the fourth and the sixth lumbar spinal canals from small holes ofvertebral arch which was made by mini-drill. Benzylpenicillinpotassium(penicellin G potassium Meiji; Meiji Seika) was dropped into the incisedpart and injected into femor muscle. Muscle and skin of the incised partwere closed by surgical suture. Sutured part was painted with iodinetincture.

A sham-operated rat was made by the above described method except forthe insertion of silicon rubber.

<Examination of Walking Ability>

The walking ability was examined by using the treadmill apparatus.

The rats were put on the running belt, and adapted to the conditionwhere the grid was sent an electric current (0.04 mA-4 mA) for threeminutes or more. Animals were forced to walk by an initial speed of 10m/min, which was gradually increased by 5 m/min at 3 min intervals.Electric stimulation (0.04 mA-4 mA) was given to the rats that stoppedwalking and moved to the grid for electric stimulation equipped in frontof the running belt. The distance between the point to walk and thepoint to give up walk, in other words, the point where it is impossiblefor them to walk even though the stimulation (sound, contact andelectricity) to make them walk was given, was measured with themileometer built into the equipment. The walking training was performedonce a day for three consecutive days before the operation. After theoperation, aldose reductase inhibitors,5-[(1Z,2E)-2-methylphenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid (in FIG. 1, Compound A; generic name: epalrestat),(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidine]-1,2′,3,5′-tetrone(in FIG. 2, Compound B; AS-3201), or(2S,4S)-6-fluoro-2′,5′-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4′-imidazoline]-2-carboxamide(in FIG. 2, Compound C; SNK-860; generic name: fidarestat), wasadministered orally for 11 days. On the other hand,carboxymethylcellulose or toragacanth gum was administered as a negativecontrol. The results obtained from the compounds- and negativecontrol-groups were analyzed by the Dunnett's multiple comparison test(*P<0.05). FIG. 1 and FIG. 2 show the results.

<Results>

The gait disturbance model by cauda equina compression is reported as amodel for the spinal canal stenosis. The compounds (Compound A, B or C)used for this invention improved the walking dysfunction in the gaitdisturbance model by cauda equina compression as shown in FIG. 1 andFIG. 2. That is, it was suggested that the compounds with the inhibitionof the aldose reductase used for this invention could be effective forthe treatment of the spinal canal stenosis.

FORMULATION EXAMPLE 1

The following components were admixed in a conventional method andpunched out to obtain 100 tablets each containing 50 mg of the activeingredient. Epalrestat (Compound A) 5.0 g Carboxymethyl cellulosecalcium (disintegrating agent) 0.2 g Magnesium stearate (lubricant) 0.1g Microcrystalline cellulose 4.7 g

FORMULATION EXAMPLE 2

The following components were admixed in a conventional method, and thesolution was sterilized in a conventional method, placed at 5 ml intoampoules and freeze-dried in a conventional method to thereby obtain 100ampoules each containing 20 mg of the active ingredient. Epalrestat(Compound A) 5.0 g Mannitol 20 g Distilled water 500 ml

1. A method for prevention and/or treatment of spinal canal stenosis,which comprises administering to a mammal in need thereof an effectiveamount of an aldose reductase inhibitory compound.
 2. The methodaccording to claim 1, wherein the spinal canal stenosis is cervicalspinal canal stenosis, thoracic spinal canal stenosis, lumbar spinalcanal stenosis or wide spinal canal stenosis.
 3. The method according toclaim 1, wherein the method is used for improving paralysis,hypoesthesia, pain or numbness.
 4. The method according to claim 1,wherein the method is used for improving physical ability.
 5. The methodaccording to claim 4, wherein the method for improving physical abilityis used for improving reduction of muscle power, intermittentclaudication and gait disability.
 6. The method according to claim 1,wherein the method is used for improving dysuria or dyschezia.
 7. Themethod according to claim 1, wherein the aldose reductase inhibitorycompound is represented by formula (I):

wherein 1) R^(1a) and R^(2a) are the same or different and eachrepresents phenyl which may be substituted by at least one groupselected from the following (1)-(10): (1) halogen, (2) trifluoromethyl,(3) hydroxyl, (4) nitro, (5) carboxyl, (6) amino which may besubstituted by C1-4 alkyl, (7) C1-4 alkyl, alkoxy or alkylthio, (8)phenyl, (9) a heterocyclic group containing at least one atom selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom, which may besubstituted by at least one group selected from (a) halogen, (b)trifluoromethyl, (c) phenyl, (d) nitro, (e) hydroxyl, (f) carboxyl, (g)amino which may be substituted by C1-4 alkyl, (h) C1-4 alkyl, (j) C1-4alkoxy, and (k) C1-4 alkyl (10) C1-4 alkyl substituted by at least onesubstituent selected from hydroxyl, phenyl, and the heterocyclic groupdescribed above (9), 2) R^(1a) is hydrogen and R^(2a) is the following(1)-(6): (1) C4-7 cycloalkyl or cycloalkenyl which may be substituted byat least one C1-4 alkyl, (2) anthryl or naphthyl, (3) phenyl which maybe substituted by at least one group selected from the following(a)-(k): (a) halogen, (b) trifluoromethyl, (c) hydroxyl, (d) nitro, (e)carboxyl, (f) amino which may be substituted by C1-4 alkyl, (g) C1-4alkyl, alkoxy or alkylthio, (h) phenyl, (j) a heterocyclic groupcontaining at least one atom selected from a nitrogen atom, a sulfuratom and an oxygen atom, which may be substituted by at least one groupselected from (i) halogen, (ii) trifluoromethyl, (iii) phenyl, (iv)nitro, (v) hydroxyl, (vi) carboxyl, (vii) amino which may be substitutedby C1-4 alkyl, (viii) C1-4 alkyl, (ix) C1-4 alkoxy, and (x) C1-4alkylthio, (k) C1-4 alkyl substituted by at least one substituentselected from hydroxyl, phenyl, and the heterocyclic group describedabove (j), (4) a heterocyclic group containing at least one atomselected from a nitrogen atom, a sulfur atom and an oxygen atom, whichmay be substituted by at least one group selected from the following(a)-(k): (a) halogen, (b) trifluoromethyl, (c) phenyl, (d) nitro, (e)hydroxyl, (f) carboxyl, (g) amino which may be substituted by C1-4alkyl, (h) C1-4 alkyl, alkoxy or alkylthio, (j) oxo, or (k) C1-4 alkylsubstituted by at least one substituent selected from hydroxyl, phenyl,and the heterocyclic group described above (j) in (3),

wherein R^(4a) is hydrogen or C1-4 alkyl, or

3) R^(1a) taken together with R^(2a) is tetramethylene or pentamethlene;R^(3a) is (1) hydrogen, (2) C1-12 alkyl, (3) C7-13 aralkyl, (4) C4-7cycloalkyl or cycloalkenyl which may be substituted by at least one C1-4alkyl, (5) phenyl which may be substituted by at least one groupselected from the following (a)-(k): (a) halogen, (b) trifluoromethyl,(c) hydroxyl, (d) nitro, (e) carboxyl, (f) amino which may besubstituted by C1-4 alkyl, (g) alkoxy or alkythio which may besubstituted by C1-4 alkyl, (h) phenyl, (j) a heterocyclic groupcontaining at least one atom selected from a nitrogen atom, a sulfuratom and an oxygen atom, which may be substituted by at least one groupselected from (i) halogen, (ii) trifluoromethyl, (iii) phenyl, (iv)nitro, (v) hydroxyl, (vi) carboxyl, (vii) amino which may be substitutedby C1-4 alkyl, (viii) C1-4 alkyl, (ix) C1-4 alkoxy, and (x) C1-4alkylthio, and, (k) C1-4 alkyl substituted by at least one substituentselected from hydroxyl, phenyl, and the heterocyclic group describedabove (j), or a salt of acid thereof when R^(3a) represents hydrogen, ora solvate thereof.
 8. The method according to claim 1, wherein thealdose reductase inhibitory compound is a compound represented byformula (II):

wherein R^(1b) represents (1) hydrogen, (2) lower alkyl, (3) substitutedor unsubstituted aryl(lower alkyl), (4) substituted or unsubstitutedaryl, or (5)

wherein R^(4b) and R^(5b) are the same or different and each represents(a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) lower alkyl, (e)lower alkoxy, (f) acyl, (g) nitro, (h) amino, (i) lower alkylamino, or(j) di(lower alkyl)amino; U^(b) represents (a) oxygen, (b) sulfur, or(c) —NR^(6b)—wherein NR^(6b) represents hydrogen or lower alkyl, andV^(b) represents lower alkyl; wherein R^(2b) and R^(3b) are the same ordifferent and each represents (1) hydrogen, (2) halogen, (3) loweralkyl, (4) lower alkoxy, (5) acyl, (6) nitro, (7) amino, (8) loweralkylamino, (9) di(lower alkyl)amino, (10) allyl or (11) allyl which issubstituted by lower alkyl, lower alkoxy or acyl, or a salt thereof or asolvate thereof; a compound represented by formula (III):

wherein T^(c) represents sulfur or NH; U^(c) represents oxygen, sulfuror imino; one of V^(c) and W^(c) represents hydrogen; halogenomethyl;1H-tetrozol-5-yl; —COOR^(c) wherein R^(c) is hydrogen, alkyl,—(CH₂CH₂O)_(n)CH₃ wherein n is an integer of 1 to 113, or substitutedphenyl;

wherein R^(1c) and R^(2c) are the same or different and each representshydrogen, alkyl, —(CH₂CH₂O)_(n)CH₃ wherein n is an integer of 1 to 113;or substituted phenyl; —CH₂OR^(3c) wherein R^(3c) is hydrogen or alkyl;

wherein R^(4c) and R^(5c) are the same or different and each representshydrogen or alkyl, and the other represents hydrogen or alkyl; X^(c)represents oxygen or sulfur; Y^(c) and Z^(c) are the same or differentand each represents hydrogen, halogen, alkyl, alkoxy, or alkylthio, or asalt thereof or a solvate thereof; or a compound represented by formula(IV):

wherein R^(1d) and R^(2d) are the same or different and each representshydrogen, halogen, lower alkoxy, or halo(lower alkyl); R^(3d) represents(1) aryl or aryl(lower alkyl) which may be substituted, or (2)heterocyclic ring-(lower alkyl); R^(4d) represents carboxy or protectedcarboxy; A^(d) represents oxygen or sulfur; Y^(d) represents carbonyl,thiocarbonyl, or sulfonyl; Z^(d) represents lower alkylene, or a saltthereof or a solvate thereof.
 9. The method according to claim 7,wherein the aldose reductase inhibitory compound is5-[(1Z,2E)-2-methylphenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
 10. The method according to claim 8, wherein the aldosereductase inhibitory compound is(R)-2-(4-bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3′-pyrrolidine]-1,2′,3,5′-tetrone,(2S,4S)-6-fluoro-2′,5′-dioxospiro[3,4-dihydro-2H-1-benzopyran-4,4′-imidazolidine]-2-carboxamideor2-[3-(4-bromo-2-fluorobenzyl)-7-chrolo-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]aceticacid.
 11. The method according to claim 1, wherein the aldose reductaseinhibitory compound is (1)DL-spiro(2-fluoro-9H-fluoren-9,4′-imidazolidine)-2′,5′-dione, (2)2,7-difluoro-4,5-dimethoxyspiro[9H-fluoren-9,4′-imidazolidine]-2′,5′-dione,(3)N-[3,5-dimethyl-4-(nitromethylsulphonyl)phenyl]-2-(2-methylphenyl)acetamide,(4) N-(carboxymethyl)-7-fluoro-N-methyl-9-oxoxanthin-2-sulphoamide, (5)3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydrofuran-2-yl)propanoic acid ethylester, (6)2-formamide-3-[5′-(2-formamide-1-hydroxyethyl)-2,2′-dihydroxybiphenyl-5-yl]-3-hydroxypropyonicacid, (7)2-[3-methyl-5-(4,5,7-trifluorobenzothiazol-2-ylmethyl)-phenyl]aceticacid, (8) 2-[5-fluoro-2-[N-(3-nitrobenzyl)thiocarbamoyl]phenoxyaceticacid, (9)8′-chrolo-2′,3′-dihydrospiro[pyrrolidine-(3,6′)(5′H)-pyrro[1,2,3-de][1,4]benzoxazine]-2,5,5′-trione,(10)2-[1-(3,4-dichrolobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]aceticacid, (11)2-[4-(4,5,7-trifluorenzothiazol-2-yl)methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid, (12) 1-(benzo[b]thiophen-2-ylsulphonyl)hydantoin, (13)1-(3-bromobenzo[b]furan-2-ylsulphonyl)hydanthione, (14)3-(carboxymethyl)-1-(3-nitrobenzyl)parabanic acid, (15)1′,3′-bis(acetoxymethyl)spiro[fluoren-9,4′-imidazolidine]-2′,5′-dione,(16) 2,8-diisopropyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazine-4-aceticacid, (17)N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine),(18) (2,6-dimethylphenylsulphonyl)nitromethane, (19)N-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenyl]-1-phenyl-cyclopropane-1-carboxamide,(20)2-[3-oxo-4-(4,5,7-trifluorobenzothiazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzothiazin-2-yl]aceticacid, (21)2-[3,7-dimethylocta-2(E),6-didienyl]-2,3-epoxy-5,7-dihydroxy-6-methyl-1,2,3,4-tetrahydronaphthalene-1,4-dione,(22) 6-fluoro-2-methylspiro[chroman-4,4′-imidazolidin]2′,5′-dione, (23)(S)-6-fluorospiro(chroman-4,4′-imidazolidine)-2′,5′-dione, (24)3,4-dihydro-4-oxo-3-[[5-((trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid, (25) 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione,(26) 3-[(4-bromo-2-fluoro-phenyl)methyl]-3,4-dihydro-4-oxo-1-phthalazineacetic acid, (27) ascorbyl gamolenate, (28) ICI-10552, (29) ICI-215918,(30) JTT-811, (31) lindolrestat, (32) salfredins, (33) TJN-732, (34)TAT, (35) thiazocin-A, (36) axillarin, or (37) minalrestat.
 12. Amedicine which comprises an aldose reductase inhibitory compound incombination with at least one pharmaceutical agent selected fromprostaglandins, prostaglandin derivatives formulations, nonsteroidalanti-inflammatory drugs, vitamin compounds, muscle relaxants,antidepressants, poly ADP-ribose polymerase inhibitors, excitatory aminoacid receptor antagonists, radical scavengers, astrocyte modulators,IL-8 receptor antagonists, and immunosuppressive drugs. 13-14.(canceled)
 15. The method according to claim 1, wherein at least onepharmaceutical agent selected from prostaglandins, prostaglandinderivatives formulations, nonsteroidal anti-inflammatory drugs, vitamincompounds, muscle relaxants, antidepressants, poly ADP-ribose polymeraseinhibitors, excitatory amino acid receptor antagonists, radicalscavengers, astrocyte modulators, IL-8 receptor antagonists, andimmunosuppressive drugs is administered in combination with the aldosereductase inhibitory compound.